Synthesis and Pharmacological Evaluation of Tetrahydro-γ-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP–AMP Synthase

The
activation of cyclic GMP–AMP synthase (cGAS) by double-stranded
DNA is implicated in the pathogenesis of many hyperinflammatory and
autoimmune diseases, and the cGAS-targeting small molecule has emerged
as a novel therapeutic strategy for treating these diseases. However,
the currently reported cGAS inhibitors are far beyond maturity, barely
demonstrating in vivo efficacy. Inspired by the structural novelty
of compound 5 (G140), we conducted a structural optimization
on both its side chain and the central tricyclic core, leading to
several subseries of compounds, including those unexpectedly cyclized
complex ones. Compound 25 bearing an N-glycylglycinoyl side chain was identified as the most potent one
with cellular IC50 values of 1.38 and 11.4 μM for
h- and m-cGAS, respectively. Mechanistic studies confirmed its direct
targeting of cGAS. Further, compound 25 showed superior
in vivo anti-inflammatory effects in the lipopolysaccharide-induced
mouse model. The encouraging result of compound 25 provides
solid evidence for further pursuit of cGAS-targeting inhibitors as
a new anti-inflammatory treatment.